期刊
AGE
卷 35, 期 1, 页码 83-101出版社
SPRINGER
DOI: 10.1007/s11357-011-9333-2
关键词
Insulin receptor; Insulin-like growth factor-1 receptor; beta-Amyloid; Alzheimer's disease; Tg2576 mice
资金
- Alzheimer Forschungsinitiative e.V. [08813]
- Else-Kroner-Fresenius Stiftung [2010_A93]
- Koln Fortune
In brains from patients with Alzheimer's disease (AD), expression of insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor substrate proteins is downregulated. A key step in the pathogenesis of AD is the accumulation of amyloid precursor protein (APP) cleavage products, beta-amyloid (A beta)(1-42) and A beta(1-40). Recently, we and others have shown that central IGF-1 resistance reduces A beta accumulation as well as A beta toxicity and promotes survival. To define the role of IR in this context, we crossed neuron-specific IR knockout mice (nIR(-/-)) with Tg2576 mice, a well-established mouse model of an AD-like pathology. Here, we show that neuronal IR deficiency in Tg2576 (nIR(-/-)Tg2576) mice leads to markedly decreased A beta burden but does not rescue premature mortality of Tg2576 mice. Analyzing APP C-terminal fragments (CTF) revealed decreased alpha-/beta-CTFs in the brains of nIR(-/-)Tg2576 mice suggesting decreased APP processing. Cell based experiments showed that inhibition of the PI3-kinase pathway suppresses endosomal APP cleavage and decreases alpha- as well as beta-secretase activity. Deletion of only one copy of the neuronal IGF-1R partially rescues the premature mortality of Tg2576 mice without altering total amyloid load. Analysis of Tg2576 mice expressing either a dominant negative or constitutively active form of forkhead box-O (FoxO)1 did not reveal any alteration of amyloid burden, APP processing and did not rescue premature mortality in these mice. Thus, our findings identified IR signaling as a potent regulator of A beta accumulation in vivo. But exclusively decreased IGF-1R expression reduces AD-associated mortality independent of beta-amyloid accumulation and FoxO1-mediated transcription.
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